title: Regulation of antinucleoprotein IgG by systemic vaccination and its effect on influenza virus clearance.
abstract: Seasonal influenza epidemics recur due to antigenic drift of envelope glycoprotein antigens and immune evasion of circulating viruses. Additionally, antigenic shift can lead to influenza pandemics. Thus, a universal vaccine that protects against multiple influenza virus strains could alleviate the continuing impact of this virus on human health. In mice, accelerated clearance of a new viral strain (cross-protection) can be elicited by prior infection (heterosubtypic immunity) or by immunization with the highly conserved internal nucleoprotein (NP). Both heterosubtypic immunity and NP-immune protection require antibody production. Here, we show that systemic immunization with NP readily accelerated clearance of a 2009 pandemic H1N1 influenza virus isolate in an antibody-dependent manner. However, human immunization with trivalent inactivated influenza virus vaccine (TIV) only rarely and modestly boosted existing levels of anti-NP IgG. Similar results were observed in mice, although the reaction could be enhanced with adjuvants, by adjusting the stoichiometry among NP and other vaccine components, and by increasing the interval between TIV prime and boost. Importantly, mouse heterosubtypic immunity that had waned over several months could be enhanced by injecting purified anti-NP IgG or by boosting with NP protein, correlating with a long-lived increase in anti-NP antibody titers. Thus, current immunization strategies poorly induce NP-immune antibody that is nonetheless capable of contributing to long-lived cross-protection. The high conservation of NP antigen and the known longevity of antibody responses suggest that the antiviral activity of anti-NP IgG may provide a critically needed component of a universal influenza vaccine.
authors.affiliation: Department of Medicine, Division of Allergy, Immunology and Rheumatology, University of Rochester Medical Center, Rochester, New York 14642, USA.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Lamere
authors.forename: Amy
authors.initials: A
authors.lastname: Moquin
authors.forename: F Eun-Hyung
authors.initials: FE
authors.lastname: Lee
authors.forename: Ravi S
authors.initials: RS
authors.lastname: Misra
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Blair
authors.forename: Laura
authors.initials: L
authors.lastname: Haynes
authors.forename: Troy D
authors.initials: TD
authors.lastname: Randall
authors.forename: Frances E
authors.initials: FE
authors.lastname: Lund
authors.forename: Denise A
authors.initials: DA
authors.lastname: Kaminski
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000097:blood* / Q000276:immunology; D056738:Cross Protection; D004195:Disease Models, Animal; D006805:Human Experimentation; D006801:Humans; D007117:Immunization, Secondary / Q000379:methods; D007074:Immunoglobulin G / Q000097:blood* / Q000276:immunology; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology; D007252:Influenza Vaccines / Q000008:administration & dosage / Q000276:immunology*; D008168:Lung / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D019590:Nucleocapsid Proteins; D009976:Orthomyxoviridae Infections / Q000517:prevention & control; D016601:RNA-Binding Proteins / Q000008:administration & dosage / Q000276:immunology*; D012376:Rodent Diseases / Q000517:prevention & control; D014611:Vaccination / Q000379:methods; D022223:Vaccines, Subunit / Q000008:administration & dosage / Q000276:immunology; D014758:Viral Core Proteins / Q000008:administration & dosage / Q000276:immunology*; D019562:Viral Load
chemical_list: D000914:Antibodies, Viral; D007074:Immunoglobulin G; D007252:Influenza Vaccines; C048842:NP protein, Influenza A virus; D019590:Nucleocapsid Proteins; D016601:RNA-Binding Proteins; D022223:Vaccines, Subunit; D014758:Viral Core Proteins